Review The Role of miRNAs in Neuropathic Pain, 2023, Morchio et al

[Hutan]

Abstract
Neuropathic pain is a debilitating condition affecting around 8% of the adult population in the UK. The pathophysiology is complex and involves a wide range of processes, including alteration of neuronal excitability and synaptic transmission, dysregulated intracellular signalling and activation of pro-inflammatory immune and glial cells. In the past 15 years, multiple miRNAs–small non-coding RNA–have emerged as regulators of neuropathic pain development. They act by binding to target mRNAs and preventing the translation into proteins. Due to their short sequence (around 22 nucleotides in length), they can have hundreds of targets and regulate several pathways.

Several studies on animal models have highlighted numerous miRNAs that play a role in neuropathic pain development at various stages of the nociceptive pathways, including neuronal excitability, synaptic transmission, intracellular signalling and communication with non-neuronal cells. Studies on animal models do not always translate in the clinic; fewer studies on miRNAs have been performed involving human subjects with neuropathic pain, with differing results depending on the specific aetiology underlying neuropathic pain. Further studies using human tissue and liquid samples (serum, plasma, saliva) will help highlight miRNAs that are relevant to neuropathic pain diagnosis or treatment, as biomarkers or potential drug targets.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045079/

 

[Hutan]

I think this is an interesting paper for a few reasons.

One is that it talks about miRNAs, and specifically, miR-448, which was recently found to be elevated in a sample of people with ME/CFS.

Another is that it presents some mechanisms by which pain can become chronic (in contrast to the psychogenic 'magic' hypothesis).

 

[SNT Gatchaman]

Different miRNAs and downregulated, but see also thread Integrative miRNA–mRNA profiling of human epidermis: unique signature of SCN9A painful neuropathy (2022).

 

[Hutan]

We know of course that just having a study suggesting a link doesn't mean there is one, but it looks as though things have moved further than that with respect to miRNA and pain.



The key idea is shown in that picture. The loop of the hairpin shaped miRNA is snipped off to activate it. One side of the hairpin locks onto messenger RNA, stopping transcription.

The identified microRNAs and their putative targets belong to a wide variety of pain-relevant pathways that can be broadly classified into those related to neuronal excitability, intracellular signalling and interaction with non-neuronal cells.

So, there are those three ways that microRNAs are thought to cause pain:

• neuronal excitability - interfering with the firing across axons. MicroRNAs alter the operation of ion channels.
• intracellular signalling
• interaction with non-neuronal cells

Neuronal excitability
Here's an example for volted gate sodium channels:

Nav1.7, one of ten members of the [Volted Gate Sodium Channel] family, was shown to be targeted by miR-30b and miR-182. These miRNAs are downregulated in the [Dorsal Root Ganglion] following nerve injury, and, if administered intrathecally or injected in the DRG, respectively, they alleviate mechanical hypersensitivity [57,58]. Resveratrol, a natural polyphenol with anti-oxidant and anti-inflammatory properties, was shown to alleviate pain following [constriction injury] through miR-182 upregulation, which by inhibiting Nav1.7 may reduce neuronal excitability

Here's an example for calcium channels. It's interesting to note that calcium channels can regulate long term changes in gene expression, causing neuronal sensitisation. And a micro-RNA is downregulated after nerve injury - applying the micro-RNA down-regulates the calcium channels and so reduces pain sensitisation.

Another class of ion channels important in pain transmission are calcium channels, classified in various subtypes, which have different roles in excitable cells. Cav1.2 L-Type calcium channels regulate long-term changes in gene expression, inducing neuronal sensitisation in neuropathic pain. miR-103 modulates three Cav1.2 subunits (Cav1.2-α1, α2δ1 and β1) in spinal cord neurons, promoting mRNA decay. miR-103 is downregulated following nerve injury, concomitant with the upregulation of Cav1.2. Additionally, delivery of miR-103 mimic after SNL reduces pain sensitisation via Cav1.2 downregulation [17].

Potassium channels too can be affected. They are responsible for allowing a neuron to return to a resting state after firing. MicroRNAs targeting potassium channels have been found to be upregulated after nerve injury:

More recently, Kv1.2 has been shown to be downregulated by miR-137a in neuropathic pain, contributing to pain hypersensitivity [38]. The authors have shown that cultured nociceptors from rats with [constriction injury] to the sciatic nerve display reduced potassium currents and increased neuronal excitability, which was rescued in nociceptors from rats treated with miR-137 antagomir. miR-137 inhibition following [constriction injury] resulted in increased Kv1.2 protein expression and pain relief [38].

Another potassium channel, TREK1, is regulated by miR-183. TREK1 is a mechano- and temperature-sensitive channel and contributes to the initiation of action potentials in C-fibres [101]. miR-183 is downregulated following nerve injury, whilst TREK1 is upregulated. miR-183 administration alleviates neuropathic pain through the inhibition of TREK1 [75].

There are more examples.

 

[Hutan]

Synaptic transmission
As well as neuronal excitability, miRNAs can change the way the signal is transmitted to the next neuron. For example, a chemotherapy drug upregulated an miRNA, which reduced an enzyme necessary for the production of GABA. The GABA was needed for inhibiting the signal. So the drug resulted in an increase in pain signals, via the increase in the miRNA.

miR-500 is involved in chemotherapy-induced neuropathy, targeting GAD67, an enzyme necessary for the synthesis of GABA in inhibitory interneurons in the dorsal horn of the spinal cord. After paclitaxel injection, miR-500 was upregulated, causing a downregulation of GAD67. This resulted in a loss of inhibitory inputs, leading to an increase in excitatory nociceptive signals [25].

They might also be causing neuronal cell death:

Indeed, several miRNAs have already been linked to neuronal cell death in neurological diseases such as Alzheimer’s [105], neuroblastoma [106] and ischemic disease [107].

Intracellular signalling
There are lots of examples of this sort of impact. Here's one:

Another important signalling pathway in the context of neuropathic pain is mediated by p38 activation in spinal microglia, following cellular stress and binding of inflammatory mediators to extracellular receptors [112]. Phosphorylated p38 is translocated into the nucleus where it activates transcription factors, such as NF-kB and STAT3, promoting the expression of inflammatory mediators such as TNFα and IL-1β [108].

Several regulators and downstream targets of p38 are targeted by miRNA. For example, miR-15/16 targets GRK2, a G-protein coupled receptor (GPCR) that inhibits p38. This miRNA cluster is upregulated following CCI in rats and its inhibition leads to reduced hyperalgesia, increased GRK2 expression and decreased phosphorylation of p38 and NF-kB p65. GRK2 knockdown leads to the abrogation of mir-15/16 inhibition, including restoration of p-p38 and p-NF-kB levels [26].

Two miRNAs are upregulated after a chronic constriction injury, reducing the expression of a G-protein coupled receptor and so increasing the activation of p38 and the subsequent expression of inflammatory molecules.

and another, also increasing p38 activation:

miR-155 is also upregulated in neuropathic pain induced by the chemotherapeutic agent Bortezomib, causing increased JNK and p38 phosphorylation [113]. Inhibition of miR-155 causes a reduction in the behavioural response to mechanical stimuli and restoration of JNK and p38 phosphorylation levels [113].